Heart or cardiac failure is defined as the pathological "state in which an abnormality of cardiac function is responsible for failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues . . . and is frequently caused by a defect (decrease) in myocardial contraction." (Hurst, Willis J. (ed) 1990 The Heart, McGraw Hill Inc., New York, 388-440).
Heart failure is characterized by decreased cardiac contractility, i.e., inotropy. The causes are well known in the art. The mechanism is generally considered to be a reduction in the the force of contraction and may be directly attributed to a decreased contractile response of cardiac myocytes. Changes in cardiac myocytes from failing hearts include: increased oxygen consumption, decreased mitochondrial mass, oxidative phosphorylation, reduced intracellular calcium, sarcomere "overstretching", decreased myosin and myofibrillar ATPase activity, changes in myosin isoforms, and reduced .alpha.,.beta.-adrenoreceptors and .alpha.,.beta.-adrenergic signalling (Braunwald, E., Textbook of Cardiovascular Disease, W. B. Saunders Co., Philadelphia, Pa. (1994)).
Approaches to the treatment of heart failure have included: reducing the workload of the heart, reducing salt intake, diuretics, inotropic agents such as digitalis, and vasodilators.
Other approaches for primary treatment of reduced contractility in heart failure include drugs which: inhibit Na/K ATPase, such as digitalis glycosides; stimulate cAMP accumulation, such as .beta.-adrenergic agonists and phosphodiesterase inhibitors; and increase myofilament sensitivity to calcium. In myocarditis, steroids and antibiotics have been used (Braunwald, E., Textbook of Cardiovascular Disease, 1990). The primary drawbacks of these methods has been lack of insufficient inotropic response, toxic effects during prolonged use, and loss of efficacy over time. Studies have shown that in spite of such primary treatments heart failure often persists with progression to death or, when possible, cardiac transplantation.
Even though various methods have been developed to treat heart failure, no single method has been found to be universally applicable and have a high therapeutic success rate. Heart failure remains one of the leading causes of death in the United States. Accordingly, there is a need to develop more efficacious therapies for the treatment of heart failure.
Recently, evidence that increases in myocyte cyclic guanosine-3',5'-monophosphate (cGMP) content concentration may contribute to reduced contractility in certain forms of heart failure has come to light. cGMP, a secondary messenger, has been shown to reduce the contractility of the heart and isolated cardiac myocytes (Atanassova, et al., (1995) J. Pharm. 44:663-666; Ballingand et al., (1993), Journal of Clinical Investigation 91(5):2314-2319; Balligand et al., (1993) PNAS 90(1)347-51). cGMP activates cGMP-dependent protein kinase (PkG). This leads to: 1) decrease in myofilament sensitivity to calcium via phosphorylation of troponin; and 2) reduction in intracellular calcium due to activation of sarcolemmal Ca.sup.2+ -ATPase and inhibition of voltage-dependent calcium channels by phosphorylations (Lincoln, T. M., and Cornwell, T. L., (1991) Blood Vessels 28:129-137).
The intracellular concentration of cGMP is regulated by cGMP-forming enzymes, i.e., guanylyl cyclases, and CGMP-degrading enzymes, i.e., CGMP phosphodiesterases. Soluble guanylyl cyclase, a cytosolic enzyme, which catalyzes the formation of cGMP from GTP, is an obligate heterodimer (.alpha./.beta.) with an associated heme group (Wong, S. K. -F. and Garbers, D. L., (1992) J. Clin. Invest. 90:299-305; Baughler, J. M., et al. (1979) Proc. Natl. Acad. Sci. 76:219-222). Soluble guanylyl cyclase is activated by a variety of endogenously formed agonists, i.e., nitric oxide (NO), carbon monoxide (CO), hydroxyl radicals (OH), and possibly hydrogen peroxide (H.sub.2 O.sub.2) (Schmidt, H. H. H. W., et al., (1991). Proc.Natl.Acad.Sci. USA, 88: 365-369; Schmidt, H. H. H. W., (1992) FEBS 307(1): 102-107).
Recent reports suggest that these endogenously formed activators are increased in various forms of heart failure, especially but not confined to those associated with inflammation (myocarditis and acute rejection associated with transplantation). Enhanced basal NO production has been reported both in human heart failure (Calver, A., (1994) Lancet 344(8919):371-3; Winlaw, D. S. et al., (1994) Lancet 344(8919):373-4) and animal models (Yang, X. et al., J. Clin. Invest. 94(2):714-21; O'Murchu, B. et al., (1994) J. Clin. Invest. 93(1):165-71). Increased production of oxygen free radicals by polymorphonuclear leukocytes, which infiltrate the myocardium, has been described in humans with congestive heart failure (Chen, L. et al., (1992) Canadian J. Cardiol. 8(7):756-60; Slungaard, A., (1991) J. Exper. Med. 173(1):117-26, line 13, p. 3). Increased oxidant stress, i.e., formation of H.sub.2 O.sub.2 and oxygen free radicals has been detected in both inflammatory and dilated cardiomyopathies (Singh, N. et al., (1995) Mol.Cell.Biochem. 147:77-81). Heme oxygenase, an enzyme which forms CO from heme, has been shown to be induced in myocarditis (Ewing, J. F., (1994) J.Pharm.Exp.Ther. 271(1):408-14).
Selective inhibition or activation of enzyme pathways involved in the metabolism or catabolism of pharmacologically active compounds, such as cGMP, is well accepted in the pharmaceutical therapy of diseases. For the effective treatment of any given disease, targeting of the appropriate pathway(s) is key. The effect that modifying the activity of a given enzymatic pathway will have upon the disease in tissue or upon a subject receiving an enzyme activity modifier is unpredictable.
Glasky et al. (U.S. Pat. No. 5,447,939) recently discovered that guanylyl cyclase modifiers could be used to treat neurological disorders. The patent claims a method for treating neurological disorders by administering "a carbon monoxide dependent guanylyl cyclase modulating purine derivative." The disorders claimed are epilepsy, seizures, peripheral neuropathy, learning disability, cerebral palsy, psychiatric disorder, memory disorder and Huntington's disease.
Tetrapyrroles, in particular porphyrins and related compounds, have several known uses. Aizawa et al. (U.S. Pat. No. 4,997,639) discloses and claims a method for detecting cholesterol deposited in a mammal. The method involves administering a porphyrin carboxylic acid to the mammal, exposing the mammal to a light source and observing the fluorescence emitted from an area in which cholesterol is deposited.
R. T. Gordon (U.S. Pat. No. 4,829,984) discloses and claims a method for improvement of transplanting organs and preserving tissues. The method involves introducing particles (made from tetrapyrroles and metallotetrapyrroles) to the tissue, allowing time for intracellular accumulation of the particles, subjecting the tissue to a pulsing electromagnetic field, and allowing time to destroy cells mediating an immunological response.
Administration of tetrapyrroles has been found to be an effective treatment for several diseases. H. L. Narisco (U.S. Pat. No. 5,298,018) discloses and claims photodynamic therapy as a method for the treatment of cardiovascular disease, specifically atherosclerosis, by, first, administration of a photosensitizing agent, such as a porphyrin, to a mammal and, second, exposing of the mammal to a light source.
Vincent et al. (U.S. Pat. No. 5,422,362) discloses and claims a method of inhibiting restenosis. The method involves administering to a subject a "green" porphyrin without having to expose the subject to a light source.
In normal subjects, Sn-protoporphyrin IX has only been reported to lower serum bilirubin levels, decrease biliary bilirubin output, and enhance biliary heme excretion (Berlund, et al., (1988) Hepatology 8(3), 625-631). Sn-protoporphyrin has been used in the treatment of various rare diseases, i.e., Crigler-Najjar Disease (Rubaltelli, F. F., (1989) Pediatrics 84(4):728-731) and Gilbert's syndrome (Anderson, K. E., (1986) CLin.Pharmacol.Ther. 39:510-20), and has, therefore, been already approved for humans. As a result, it is believed to be relatively safe and the risk/benefit in severe heart failure acceptable.
Recent evidence suggests that porphyrins, particularly metalloporphyrins, interact at a common binding site on guanylyl cyclase. Some porphyrins and metalloporphyrins inhibit (Sn-protoporphyrin IX, Zinc-protoporphyrin IX, Manganese-protoporphyrin IX, N-Phenylprotoporphyrin IX, Deuteroporphyrin IX dimethyl ester, Hematoporphyrin IX dimethyl ester, Deuteroporphyrin IX disulfonate, Deuteroporphyrin IX bisglycol, and Coproporphyrin I) while others stimulate (Protoporphyrin IX, Mesoporphyrin IX, Hematoporphyrin IX, Deuteroporphyrin IX, Coproporphyrin III, Protoporphyrin IX dimethyl ester, and N-Methylprotoporphyrin IX) guanylyl cyclase (Ignarro, L. J., (1994) Advances in Pharmacology, 26:35-65).
Although porphyrins and metalloporphyrins are known to be useful in the treatment of several diseases and guanylyl cyclase modifiers are known to be useful in the treatment of neurological diseases, there is no teaching or suggestion in the prior art of the present invention.
It is an object of the present invention to provide a method for treating heart failure in mammals by the administration of tetrapyrroles (Tps) or metallotetrapyrroles (MTps).
It is another object of the present invention to provide a method for treating heart failure in mammals comprising administering a Tp or MTp compound such that the compound accumulates in the cardiac myocytes of the mammal.
It is yet another object of the present invention to provide a method for treating heart failure in mammals comprising administering a Tp or MTp compound such that the compound accumulates in the cardiac myocytes at or above a minimum threshold level.
It is still yet another object of the present invention to provide a method for treating heart failure in mammals further comprising readministering the compound once the compound accumulation in the cardiac myocytes drops below a minimum threshold level.
It is a further object of the present invention to provide a method for treating heart failure in mammals comprising administering a Tp or MTp compound such that the compound inhibits guanylyl cyclase activity in the cardiac myocytes.
It is a still further object of the present invention to provide a method for treating heart failure in mammals, where the method comprises administering a Tp or MTp compound in discrete doses and/or in slow, controlled or sustained release doses such that the compound accumulates in the cardiac myocytes in an amount and for a period of time sufficient to allow resolution of heart failure.
It is contemplated that administration of the Tps and MTps of this invention will be ceased upon resolution of the heart failure, heart transplantation, or determination of a suitable stable regimen of treatment not involving these Tps or MTps.
It is also contemplated that the compounds of the present invention may be used in conjunction (either simultaneously, alternately or otherwise) with other compounds typically used for the treatment of heart failure such as, by way of example and without limitation, acetylcholinesterase (ACE) inhibitors, beta-blockers and the like.
It is further contemplated that the compounds of the present invention may be administered with central or peripheral vasodilators such as, by way of example and without limitation, prazocin, hydralazine and the like.